Colorectal cancer (CRC) arises from the accumulation of genetic and epigenetic alterations in colon epithelial cells that drive normal colon epithelial cells to undergo an aberrant crypt focus→adenoma/serrated polyp→cancer progression sequence. Although virtually all CRCs arise from adenomatous polyps or serrated polyps, it is estimated that only 5% of polyps will ever progress to cancer. Identification of the factors that mediate the malignant transformation of polyps would enhance our ability to prevent CRC by allowing us to identify people at high risk for developing CRC. These individuals could then be placed on aggressive surveillance programs or receive chemoprevention therapies. Prominent risk factors for cancer are old age, smoking, obesity, and chronic inflammation. Of these factors, old age is arguably the strongest risk factor, and a number of mechanisms have been invoked including: 1) the accumulation of genetic and epigenetic alterations in aging cells, 2) "inflammaging", and 3) protumorigenic effects of senescent cells. It is widely appreciated that the rate of biological aging does not necessarily correlate with the chronological aging rate and that some individuals age biologically faster than others. Recently, it has been shown that the biological age of tissues can be determined using the methylation status of a subset of CpG dinucleotides in the human genome. These "clock CpGs" are robust indicators of biological age and reveal divergent chronological age and biological age in some individuals. We propose that accelerated and/or dysfunctional aging of the colon mucosa may mediate the malignant transformation of colon polyps and that individuals with biologically "old" colons, as determined by their clock CpG status, are at increased risk of developing advanced adenomas and CRC. We further propose that two mechanisms through which biologically older colons may be at risk of CRC are through: 1) the pro- tumorigenic effects of senescence via the senescence associated secretory phenotype (SASP) and 2) increased accumulation of aberrantly methylated genes (aka epigenetic drift). Thus, we will carry out a series of studies to determine whether the biological age of colons associate with advanced adenomas (AA) and cancer and whether the biological age of the colon predicts the likelihood of forming advanced adenomas and CRC. We will also determine whether tumorigenic effects of senescence and/or epigenetic drift are the mediators of this process. The Specific Aims of this proposal are: 1) To determine ifthe biological age of the normal colon mucosa predicts the presence of advanced colon adenomas or adenocarcinomas; 2) To determine if age-related DNA methylation is increased in biologically older colons and correlates with the presence of advanced adenomas or CRC; 3) To determine if tumorigenic effects of age related senescence mediate the increased risk of polyp→CRC transformation.